Epithelial neoplasia is frequently associated with deregulation of growth factor signaling pathways, with increasing evidence pointing to a role for insulin-like growth factors (IGFs) and the IGF-I receptor in this process. Experiments using 3T3-like fibroblast cell lines derived from IGF-IR -/- mice have revealed a remarkable resistance to transformation by numerous oncogenes, supporting the concept that IGF-IR signaling plays a central role in neoplastic transformation of this cell type. We have examined the involvement of this pathway in epithelial neoplasia using murine epidermal keratinocytes as a model system. Cell lines were generated from IGF-IR -/- and control keratinocytes following transduction with v-rasHa retrovirus. Whereas both sets of v-rasHa cell lines produced squamous tumors when grafted onto nude mice, control lines produced carcinomas while those lacking IGF-IR yielded slow- growing papillomas or occasional low-grade carcinomas. Thus, although the induction of epidermal tumors by v-rasHa is not dependent on IGF-IR function, this pathway appears to play a role in malignant progression. Several non-transformed keratinocyte cell lines have been established using epidermis from IGF-IR -/- mice and control littermates to further investigate this hypothesis.